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Asymptomatic Primary Hyperparathyroidism:
OBSERVE
Jerrod Keith, MDUniversity of Colorado General
SurgeryFebruary 25, 2008
Overview
• Primary hyperparathyroidism• Consensus statement• Long term observations• Surgery vs observation trial• Medical therapies• Conclusions
Primary Hyperparathyroidism
• Primary– Single adenoma – 80%– Diffuse hyperplasia – 15%– Multiple adenomas – 4%
• Prevalence: 0.1 – 0.5%• Incidence: 0.03%
• Asymptomatic: 80%
Classic Symptoms
• Nephrolithiasis – 20%• Fractures or radiographic findings – 2%
– Osteitis fibrosa cystica• Severe proximal myopathy• Neuropsychiatric impairment
Parathyroidectomy
• Cure rate– 95% – 98%
• Perioperative morbidity– Up to 3%
• Permanent hypoparathyroidism– 2%
• Permanent laryngeal nerve injury– <1%
Consensus Statement• NIH April, 2002• Guidelines for surgery
– Pts not willing are not able to continue surveillance
Consensus Statement
• Neuropsychological– Not possible to predict which pts will benefit
from surgery• Cardiovascular
– No associated cardiovascular abnormalities– No improvement in HTN after surgery
• GI– No associated PUD or pancreatitis
Consensus Statement
• Medical therapies: SERMs, bisphosphonates, calcimimetics– Preliminary efficacy on serum calcium and
bone density– Unknown verifiable clinical outcomes
Guidelines for Observation
• Patients not meeting surgical criteria
• Moderate calcium intake• Baseline
– Abdominal xrays or ultrasounds– Urinary Ca
• Q6 months– Serum Ca
• Annual– BMD
10-year Prospective Study
• NEJM, 1999• 121 patients with pHPT
– 101 (83%) asymptomatic• 61 underwent parathyroidectomy• 60 observed
– 52 asymptomatic• Followed over 10 years
10-year Prospective Study
• Bi-annual biochemistries• Bone mineral density annually
• Surgery recommended for those meeting NIH criteria
Patient Breakdown
Observation Arm• No significant changes from baseline
– BMD or biochemistries
• Asymptomatic postmenopausal women– No significant changes
Observation Arm
• Disease progression– Developed indication for parathyroidectomy– 14/52 asymptomatic patients– No classic symptoms developed
• renal stones• decreased creatinine clearance• fractures• hyperparathyroid crises
Study Conclusions
• Biochemistries remained stable• Bone mineral density remained stable
• Monitored pts may progress, but do not develop classic symptoms
Surgery vs Observation
• Prospective, randomized trial• 191 patients, mean age 64
– 95 observation, 96 surgical• Inclusion criteria
– Untreated, asymptomatic pHPT– Elevated serum Ca (10.4-11.4mg/dl)– Age 50 – 80 – No Ca metabolizing medications
Surgery vs Observation
• Measured outcomes– Serum calcium, albumin, creatinine, PTH– Mean arterial pressure– Bone mineral density (BMD)– Quality of life assessments
• 2 years, longitudinal data
Surgery vs Observation
• Serum biochemistries– Observation
• No significant changes over 2 years– Surgery
• Normalization of Ca and PTH postop– Creatinine
• No significant change in either group
• Mean arterial pressure– No significant changes in either group
Surgery vs Observation
• Bone mineral density– Observation
• No significant changes– Surgery
• Increase in BMD of lumbar spine• No changes in femoral neck or radius
Surgery vs Observation
• Quality of life and mental health symptoms• Short Form-36 general health survey (SF-
36)
• Results– Pts scored lower at baseline than healthy
controls– Overall no significant changes after 2 years in
either surgery or observation
PF – physiological functioning
PCS – physical component summary
RE – role emotional
MH – mental health
VIT – vitality
MCS – mental component summary
Surgery vs Observation
• Summary– Serum biochemistries, MAP, and BMD remain
stable during observation– Pts have decreased QoL and more
psychological symptoms than normal healthy controls
• No clinical significant benefit of operative treatment
Medical Therapy
• Estrogen replacement– Modest decline in serum Ca (0.5 to 1.0 mg/dl)– Improved BMD lumbar and femoral neck
• SERMs– Decline in serum Ca– Decreased levels of bone turnover markers
• Bisphosphonates• Calcimimetics
Bisphosphonates• Inhibit osteoclast-mediated bone resorption• 2 randomized, double-blind, placebo
controlled trials
• 40 pts, postmenopausal women– Alendronate vs placebo for 48 wk– Significant increase in BMD: lumbar (4.2%) and
hip (3.8%)– Significant reduction in serum Ca vs placebo
• -0.34 mg/dl vs +0.04, (P=0.018)
Bisphosphonates
• 44 pts, alendronate vs placebo– 2 years, placebo group crossover after 1 year– BMD vs baseline– Increased BMD lumbar (+6.9%), hip (+3.7%)
• P<0.001– BMD after crossover: lumbar (+4.1%), hip
(+1.7)• P=0.005
– No change in serum Ca
Calcimimetics• Increase calcium-sensing receptors in parathyroid
glands• Randomized, double-blind, placebo controlled
– 78 pts with primary hyperparathyroidism• Cinacalcet vs placebo• Primary endpoint = normocalcemia, with Ca
reduction > 0.5mg/dl
• Achieved in 73% vs 5% (P<0.001)• PTH: -7.6% vs +7.7% (P<0.01)• No change in BMD
Guidelines for Observation
• Moderate calcium intake• Baseline
– Abdominal xrays or ultrasounds– Urinary Ca
• Q6 months– Serum Ca
• Annual– BMD
Conclusions
• Serum biochemistries remains stable• Bone mineral density remains stable• No clear neuropsychiatric improvement after
surgery• Calcium metabolizing medications may be
beneficial• Disease progression w/out classic symptoms
• OBSERVATION is safe
References• Belezikian JP, Potts JT, et al. Summary statement from a workshop on
asymptomatic primary hyperparathyroidism: A perspective for the 21st century. J ClinEndocrinol Metab. 2002. 87(12):5353-61.
• Bollerslev J, Jansson S, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: A prospective, randomized trial. J Clin Endocrinol Metab. 2007. 92: 1687-1692.
• Chow CC, Chan WB, et al. Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab. 2003. 88(2): 581-587.
• Khan AA, Bilezikian JP, et al. Alendronate in primary hyperparathyroidism: A double-blind, randomized, placebo-controlled trial. J Clin Endorcinol Metab. 2004. 89(7):3319-3325.
• Peacock M, Bilezikian JP, et al. Cinacalcet hydorcholride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin EndocrinolMetab. 2005. 90(1): 135-41.
• Silverberg SJ and Bilezikian JP. The diagnosis and management of asymptomatic primary hyperparathyroidism. Nature Clinical Practice: Endocrinology & Metabolism. 2006. 2(9): 494-503.
• Silverberg SJ, Shane E, et al. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. NEJM. 1999. 341(17):